DE1164420B - Process for the preparation of nordihydro-toxiferin, of its salts with acids and of its derivatives quaternized in the 3- and / or 3'-position. - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C07d

German class: 12 ρ -11/01

Number:
File number:
Registration date:
Display day:

H 38396 IVd / 12 ρ January 16, 1960 March 5, 1964

The invention relates to a process for the preparation of nor-dihydro-toxiferin of the formula

of its salts with acids and of its in the 3- and / or 3'-position by means of reactive Esters of alkanols quaternized derivatives.

The inventive method is that 30 or

one compound of the formula process for preparation

of nor-dihydro-toxiferin, of its salts with acids and of its in

3 and / or 3 'position quaternized Derivatives

Applicant:

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel (Switzerland)

Representative:

Dr. G. Schmitt, lawyer,
Loerrach (Bad.), Friedrichstr. 3

Named as inventor:

Dr. Karl Bernauer, Kilchberg,

Dr. Paul Karrer,

Dr. Hans Schmid, Zurich (Switzerland)

Claimed priority:

Switzerland of January 30, 1959 (No. 68 972)

H ₂ CO CH CH-O-CH2

II

HO - H ₂ C CH CH CH ₂ - OH HC

or their in the 3 and / or 3 'position by means of reactive Esters of alkanols quaternized derivatives at room temperature in the presence of

409 537/551

Treated glacial acetic acid with hydrogen bromide, the resulting compound of the formula

Λ A. -H —Ι «I. V W. I!
CH Br-H ₂ C
I. CH ₂ - Br I.
HC
Μ Il
CH CH
Μ Λ Ν ³ - H

or their in the 3 and / or 3 'position by means of reactive Esters of alkanols with quaternized derivatives at room temperature Treated zinc and glacial acetic acid and optionally then obtained nor-dihydro-toxiferin with Reacts reactive esters of alkanols or converted into a salt with an acid.

As starting materials you can, for. B. Caracurin V (Formula II), Caracurin Va (Formula III) or C toxiferin dichloride use. It is advantageous to work with the exclusion of light and moisture. For the optionally subsequent quaternization of nor-dihydro-toxiferin obtained suitable reactive Esters of alkanols are e.g. B. the halides or sulfates, such as methyl iodide, methyl bromide or dimethyl sulfate. The quaternization reaction is expediently carried out in an inert solvent, z. B. benzene. For the formation of salts of nor-dihydro-toxiferin with acids one can use inorganic or organic acids, e.g. B. sulfuric acid, hydrochloric acid, hydrobromic acid, Hydroiodic acid, phosphoric acid, oxalic acid, toluenesulfonic acid, methanesulfonic acid, picric acid or tartaric acid.

The products of the process can, for. B. by chromatography or crystallization, e.g. B. about theirs poorly soluble diiodides or dipikrates.

The process products are mostly crystalline compounds, which are characterized by pronounced Distinguish effect on the nervous system; some of them, especially the bisquaternary salts, have a curative effect. They are meant to be used as remedies.

From HeIv. Chim. Acta, 41 (1958), pp. 2293 to 2308, it is known that the so-called Wieland-Gumlich glycol can be removed by treatment with hydrogen bromide in glacial acetic acid and subsequent reduction with zinc dust in glacial acetic acid into the 18-deoxy derivative leaves. However, it was not to be expected that this procedure would apply to the starting materials according to the invention connections used because there is a balance between the Caracurin Va form (with free cis hydroxyl groups) and the caracurin V-form (with masked, i.e. included in an aminoacetal grouping, Cie hydroxyl group) was to be charged. It is also known from the cited literature that that the Wieland-Gumlich aldehyde, which is the starting materials used according to the invention to the extent that the Ci8-hydroxyl group also forms part of an acetal group with him, much more difficult to convert into the 18-deoxy derivative (it is the maintenance of higher reaction temperatures and the additional use of phosphorus required) than the Wieland-Gumlich glycol, and that isomerization occurs at the side double bond. It is among these Surprisingly, the cis-hydroxyl groups according to the invention as starting material compounds used according to the methods known from Wieland-Gumlich-Glykol can be replaced by hydrogen and that the stereo configuration is retained.

This made it possible for the first time to use compounds of the Dihydrotoxiferin type To obtain partial synthesis without the

ao stereoconfiguration of the side chain is affected, as is the case with the partial synthesis, starting out from the Wieland-Gumlich aldehyde (cf. p. 2306 of the literature cited above) is the case. In the examples below, the temperatures are given in degrees Celsius.

example 1

A solution of 96 mg of caracurin V in 1 ml of glacial acetic acid is added dropwise with stirring over the course of 10 minutes in 30 ml hydrogen bromide glacial acetic acid (solution saturated at 0 °, diluted 3: 100). The yellow one The solution is stored at room temperature for 62 hours with the exclusion of light and moisture.

The reaction mixture, from which a slight precipitate has separated out, is then evaporated in vacuo at 40 °. The residue is shaken with 50 ml of glacial acetic acid and 5 g of zinc dust for 90 minutes, and after adding 10 ml of absolute methanol for a further 30 minutes. It is then filtered and the residue is washed with a large amount of methanol. The filtrate is evaporated in vacuo, the residue is dissolved in water, aqueous ammonia is added to the solution and it is then extracted exhaustively with chloroform. The chloroform extract is evaporated to dryness and the residue is chromatographed in benzene solution on 15 g of aluminum oxide (Brockmann, 12% water), the eluate (elution with benzene, fractions of 5 to 6 ml) being followed by paper chromatography and from which the nor-dihydro- Toxiferin-containing fractions 3 to 8 this is isolated by evaporating the solution. The nor-dihydro-toxiferin (24 mg) obtained is converted into dihydrotoxiferin-diiodide by treatment with methyl iodide in benzene, the latter is recrystallized from acetone-water and converted into dihydrotoxiferin dichloride on an anion exchanger based on polystyrene with quaternary ammonium groups in the chloride form, which is recrystallized twice from methanol-ether; [a]? = -605 ± 5 ° (c = 0.377; 50% ethanol). The dihydrotoxiferin dichloride obtained can be converted in the usual way into dihydrotoxiferin dipikrat, which is recrystallized once from acetone-water; F. 180 to 185 °. The quaternization reaction proceeds with practically quantitative yield.

Example 2

100 mg Caracurin Va are dissolved in 1 ml glacial acetic acid and mixed with 30 ml hydrogen bromide glacial acetic acid (at 0 ° saturated solution, diluted 3: 100) added. After standing for 60 hours at room temperature it is evaporated in vacuo and the work is carried out according to the information in Example 1. That obtained nor-dihydro-toxiferin (27 mg) is quaternized and as dihydrotoxiferin dichloride as in Example 1 by the specific rotation, also by paper chromatographic comparison with an authentic sample and by conversion into the picrate from the melting point 180 to 185 ° identified.

Example 3

100 mg of C toxiferin dichloride are dissolved in 1 ml of glacial acetic acid and 50 ml of hydrogen bromide-glacial acetic acid are added (at 0 ° saturated solution, diluted 3: 100). After standing for 60 hours at room temperature one evaporates in a vacuum. The residue is shaken for 90 minutes with 100 ml of glacial acetic acid and excess zinc dust, whereupon 20 ml of absolute methanol are added and another 30 minutes continues to shake. It is then filtered and the residue is rewashed with absolute methanol. That The filtrate combined with the washing liquid is evaporated in vacuo and the residue with water recorded. The alkaloid mixture is precipitated from the aqueous solution with aqueous picric acid solution, whereupon the picrates are converted into the corresponding chlorides on an ion exchanger will. The dihydrotoxiferin dichloride (about 25 mg) is made by crystallization from n-propanol separated, purified by dissolving from methanol ether and identified as in Example 2.

Caracurin-V-dimethochloride can also be used in a similar procedure convert to dihydrotoxiferin dichloride.

Claims (1)

Claim: Process for the preparation of nordihydrotoxiferin of the formula characterized in that a compound of the formula 55 60 of its salts with acids and of its derivatives quaternized in the 3- and / or 3'-position by means of reactive esters of alkanols, H ₂ CO-CH CH-O-CH2 HO - H ₂ C CH CH CH ₂ - OH III HC or their quaternized in the 3 and / or 3 'position by means of reactive esters of alkanols Derivatives treated with hydrogen bromide at room temperature in the presence of glacial acetic acid, the resulting compound of the formula Br _{- H 2} C CH CH CH ₂ - Br HC IV or their quaternized in the 3 and / or 3 'position by means of reactive esters of alkanols Derivatives are then treated with zinc and glacial acetic acid at room temperature and, if appropriate, subsequently obtained nor-dihydro-toxiferin with reactive esters of alkanols or with an acid in a Salt transferred. Publications considered: Helvetica Chimica Acta, 37 (1954), pp. 1993 ff .; (1958), pp. 2293-2308. A priority document was displayed when the registration was announced.